Out-of-hospital cardiac arrest (OHCA) remains one of the leading causes of death in the United States. Even with the best clinically documented methods of cardiopulmonary resuscitation (CPR) and post-resuscitation care, more than 85-90% of the 350,000 Americans with OHCA die or have severe neurological deficits. Despite intensive research, little or no improvement in outcomes has been observed for over half a century. This application is focused on treating cardiac arrest patients that have been successfully defibrillated during the post-resuscitation phase. There remains a tremendous opportunity to optimize and improve the care of these patients, during the period of time when there is maximal hemodynamic instability and when the processes the result in neurologic damage begin to impact the ultimately outcome. In this application we propose to test the hypothesis that neurological recovery during the post-resuscitation phase will improve by non-invasively modulating cerebral perfusion and brain electrical activity with brain-specific intrathoracic pressure regulation (IPR) therapy in the first 12 hours after cardiac arrest. IPR therapy was developed by our research group and relies on active withdrawal of air from the lungs to create a small sub-atmospheric pressure during the expiratory phase of the typical positive pressure ventilation cycle. It has been demonstrated to increase hemodynamics, cerebral perfusion and blood flow in shock and brain injured states, and neurologically intact survival when used during CPR. Our intent is to demonstrate proof of preclinical concept that non-invasive brain-specific-IPR modulation of intracranial pressure and cerebral blood flow will improve processed EEG signals and neurological functional outcomes after cardiac arrest and return of spontaneous circulation (ROSC). As such, the specific aim of this proposal is to determine the safety and efficacy of two different levels of IPR therapy compared to no IPR therapy on hemodynamics, cerebral blood flow, ICP and EEG signals during the interval between ROSC and 12 hours post-ROSC and to correlate findings with brain histopathology and neurologically intact survival at 48 hours in a porcine model. If successful, IPR therapy will result in a novel post- resuscitation treatment and will effectively bridge the link between ROSC and long-term neurological function, significantly improving neurological survival and quality of life post cardiac arrest.